Abstract |
The activator protein-1 (AP-1) transcription factor, comprising Jun and Fos family proteins, distinctly regulates various cellular processes, including those involved in inflammation. FOS like antigen 1 (Fra-1), a member of the Fos family, dimerizes with members of the Jun family and regulates gene expression in a context-dependent manner. Although respiratory toxicants are known to stimulate the expression of Fra-1 in the lung, whether Fra-1 promotes or decreases susceptibility to the development and progression of toxicant-induced lung disease in vivo is not well established. To determine the role of Fra-1 in LPS-induced acute lung injury and mortality, we administered LPS either intraperitoneally or intratracheally to Fra-1-sufficient (Fra-11(+/+)) and Fra-1-deficient (Fra-1(Δ/Δ)) mice. LPS-induced mortality, lung injury, inflammation, cytokine measurements, and AP-1 and NF-κB activities were then assessed in these mice. Fra-1(Δ/Δ) mice showed a greater resistance to LPS-induced mortality than did their Fra-1(+/+) counterparts. Consistent with this result, LPS-induced lung injury and inflammatory responses were markedly lower in Fra-1(Δ/Δ) mice than in Fra-1(+/+) mice. Compared with Fra-1(+/+) mice, Fra-1(Δ/Δ) mice showed a reduced influx of neutrophils into the lungs, accompanied by a decreased expression of proinflammatory cytokines in response to treatment with LPS. The decreased inflammatory responses in Fra-1(Δ/Δ) mice coincided with diminished and increased levels of NF-κB and c-Jun/AP-1 binding, respectively. These results demonstrate that Fra-1/AP-1 plays a key role in promoting LPS-induced injury and mortality in mice, and they suggest that targeting (i.e., inhibiting) this transcription factor may be a useful approach to dampening the adverse effects of exposure to endotoxins.
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Authors | Michelle Vaz, Narsa M Reddy, Subbiah Rajasekaran, Sekhar P Reddy |
Journal | American journal of respiratory cell and molecular biology
(Am J Respir Cell Mol Biol)
Vol. 46
Issue 1
Pg. 55-62
(Jan 2012)
ISSN: 1535-4989 [Electronic] United States |
PMID | 21816965
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cytokines
- Lipopolysaccharides
- NF-kappa B
- Proto-Oncogene Proteins c-fos
- Proto-Oncogene Proteins c-jun
- Transcription Factor AP-1
- Transcription Factors
- fos-related antigen 1
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Topics |
- Acute Lung Injury
(chemically induced, genetics, metabolism)
- Animals
- Cytokines
(genetics, metabolism)
- Gene Expression Regulation
- Inflammation
(genetics, metabolism)
- Lipopolysaccharides
- Mice
- NF-kappa B
(genetics, metabolism)
- Neutrophils
(metabolism)
- Proto-Oncogene Proteins c-fos
(genetics, metabolism)
- Proto-Oncogene Proteins c-jun
(genetics, metabolism)
- Transcription Factor AP-1
(genetics, metabolism)
- Transcription Factors
(genetics, metabolism)
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